The abnormal pattern of visual evoked responses (VERs) in rabbits with hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF) resembles that associated with coma induced by a barbiturate, a benzodiazepine (BZ) or a gamma-amino-butyric acid (GABA) agonist. As these drugs induce neural inhibition by potentiating GABAergic inhibitory neurotransmission as a consequence of their interaction with specific binding sites on the GABA/BZ receptor complex on postsynaptic neural membranes, these findings suggest that the pattern of neuronal activity in HE may resemble that associated with activation of the GABA inhibitory neurotransmitter system. To take account of the rapid metabolism of GABA, a modified Oldendorf technique, which employed the use of a vascular marker, has been used to demonstrate that the brain uptake index of plasma GABA is increased in the rabbit model of HE. Ameliorations of HE (both clinical and electrophysiologic (VER waveform)) were induced in rabbits with FHF by a GABA receptor antagonist, a BZ receptor antagonist and a chloride channel blocker and in rats with FHF by a BZ receptor antagonist and a partial inverse agonist of the BZ receptor. The spontaneous activity of Purkinje neurons of rabbits in HE exhibited increased sensitivity to depression by a GABA agonist and a BZ agonist, but was excited by BZ receptor antagonists. These findings suggest that in HE due to FHF: (i) There is increased GABAergic tone which is neither species nor model dependent; (ii) Blockading GABA or BZ receptors ameliorates HE; (iii) BZ receptor antagonists may be of clinical value in treating HE; and (iv) An endogenous BZ receptor agonist may contribute to HE.